Adela R. Cardones

Immune Evasion by Murine Melanoma Mediated through CC Chemokine Receptor-10

Human melanoma cells frequently express CC chemokine receptor (CCR)10, a receptor whose ligand (CCL27) is constitutively produced by keratinocytes. Compared with B16 murine melanoma, cells rendered more immunogenic via overexpression of luciferase, B16 cells that overexpressed both luciferase and CCR10 resisted host immune responses and readily formed tumors. In vitro, exposure of tumor cells to CCL27 led to rapid activation of Akt, resistance to cell death induced by melanoma antigen-specific cytotoxic T cells, and phosphatidylinositol-3-kinase (PI3K)–dependent protection from apoptosis induced by Fas cross-linking. In vivo, cutaneous injection of neutralizing antibodies to endogenous CCL27 blocked growth of CCR10-expressing melanoma cells. We propose that CCR10 engagement by locally produced CCL27 allows melanoma cells to escape host immune antitumor killing mechanisms (possibly through activation of PI3K/Akt), thereby providing a means for tumor progression.

VEGF Inhibitors in Cancer Therapy

Vascular endothelial growth factor (VEGF)-mediated angiogenesis is thought to play a critical role in tumor growth and metastasis. Consequently, anti-VEGF therapies are being actively investigated as potential anti-cancer treatments, either as alternatives or adjuncts to conventional chemo or radiation therapy. Among the techniques used to block the VEGF pathway are: 1) neutralizing monoclonal antibodies against VEGF or its receptor, 2) small molecule tyrosine kinase inhibitors of VEGF receptors, 3) soluble VEGF receptors which act as decoy receptors for VEGF, and 4) ribozymes which specifically target VEGF mRNA. Recent evidence from phase III clinical trials led to the approval of bevacizumab, an anti-VEGF monoclonal antibody, by the FDA as first line therapy in metastatic colorectal carcinoma in combination with other chemotherapeutic agents. However, may challenges still remain, and the role of anti-VEGF therapy in the treatment of other solid tumors remains to be elucidated. The aim of this article is to review the progress of clinical investigations involving VEGF inhibitors in the treatment of different types of solid tumors.

Cutaneous squamous cell carcinoma and human papillomavirus: is there an association?

BACKGROUND The role of human papillomavirus (HPV) in the induction and maintenance of cervical, anogenital, and some oropharyngeal carcinomas is well recognized, but its role in cutaneous squamous cell carcinoma (SCC) remains to be elucidated. HPV is thought to act as a possible cocarcinogen in the development of SCC. OBJECTIVE To review the literature assessing the correlation between and possible causation of HPV and cutaneous SCC in immunocompetent and immunocompromised populations. METHODS We reviewed HPV sampling and detection methods, epidemiologic studies examining HPV carriage in immunocompetent and immunosuppressed individuals, and evidence asserting an association between HPV and cutaneous SCC. RESULTS Although an abundant body of evidence points toward a link between HPV and cutaneous SCC, many studies indicate otherwise. Recent studies have focused on viral activity in addition to DNA presence. CONCLUSION The possibility exists that HPV may play a role in the induction but not maintenance of cutaneous SCC.

α-Melanocyte-Stimulating Hormone–Induced Eruptive Nevi

BACKGROUND Synthetic peptides that target proopiomelanocortin receptors are being investigated as a novel and safe way to tan. It has been postulated that synthetic alpha-melanocyte-stimulating hormone (alpha-MSH) peptides may have protective effects against the development of melanoma because of their melanogenic activity. Their ultimate biological effect, however, especially in patients with dysplastic nevi or previous melanoma, has yet to be determined. OBSERVATIONS A 40-year-old white man with a history of melanoma and multiple dysplastic nevi self-administered synthetic alpha-MSH. He developed crops of new pigmented nevi, many of which had atypical clinical and histopathologic features. The preexisting nevi became darker and acquired growth features. After alpha-MSH use was discontinued, the nevi progressively lightened and lost their growth features. CONCLUSIONS Synthetic alpha-MSH peptides can drive proliferation of neoplastic melanocytic cells in predisposed patients. This could present an increased risk for melanoma development.

WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4

WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling.

Oncostatin M enhances CCL21 expression by microvascular endothelial cells and increases the efficiency of dendritic cell trafficking to lymph nodes.

CCL21, a lymphatic endothelial cell (LEC)-derived chemokine, and its receptor CCR7 regulate dendritic cell (DC) trafficking to lymph nodes (LN), but it is unclear how CCL21 expression is regulated. Oncostatin M (OSM) is an IL-6-like cytokine synthesized by activated DC and other leukocytes. In vitro, OSM (but not TNF-α) stimulated CCL21 mRNA and protein expression by human dermal microvascular EC (DMEC) in an ERK1/2-dependent fashion. Conditioned medium from OSM-treated DMEC stimulated CCL21-dependent chemotaxis of mouse bone marrow-derived DC (BMDC). Cultured BMDC expressed OSM, which was increased with the addition of LPS. Topical application of the contact-sensitizing hapten, trinitrochlorobenzene, resulted in enhanced OSM expression in the skin, whereas cutaneous injection of TNF-α did not. Injection of OSM into the footpad increased CCL21 mRNA expression in the draining LN by ∼10-fold and in mouse skin by ∼4-fold without increasing CCR7 mRNA. In vitro, OSM increased the permeability of DMEC and lung microvascular EC monolayers to FITC-dextran beads, and, in vivo, it enhanced accumulation of Evans blue dye in draining LN by ∼3-fold (p = 0.0291). Of note, OSM increased trafficking of BMDC injected in footpads to draining LN by 2-fold (p = 0.016). In summary, OSM up-regulates CCL21 expression in skin and draining regional LN. We propose that OSM is a regulator of CCL21 expression and endothelial permeability in skin, contributing to efficient migration of DC to regional LN.

Preliminary Results on the Feasibility of Using ARFI/SWEI to Assess Cutaneous Sclerotic Diseases.

In this study, acoustic radiation force impulse (ARFI) and shear wave elasticity imaging (SWEI) were applied to the skin to investigate the feasibility of their use in assessing sclerotic skin diseases. Our motivation was to develop a non-invasive imaging technology with real-time feedback of sclerotic skin disease diagnosis. This paper shows representative results from an ongoing study, recruiting patients with and without sclerosis. The stiffness of the imaged site was evaluated using two metrics: mean ARFI displacement magnitude and bulk shear wave speed inside the region of interest (ROI). In a subject with localized graft versus host disease (GVHD), the mean ARFI displacement inside sclerotic skin was 61% lower (p < 0.01) and shear wave speed 128% higher (p < 0.005) compared to those in normal skin-indicating stiffer mechanical properties in the sclerotic skin. This trend persisted through disease types. We conclude ARFI and SWEI can successfully differentiate sclerotic lesions from normal dermis.

Management of dermatitis herpetiformis.

The major treatment strategies for DH are gluten restriction or medical treatment with sulfones. Control of the cutaneous manifestations, but not the gastrointestinal changes, is rapid with dapsone. In addition to control of the cutaneous signs and symptoms of DH, dietary gluten restriction also induces improvement of gastrointestinal morphology and is possibly protective against the development of lymphoma.

Vascularized composite allotransplantation: a closer look at the banff working classification

The first Banff vascularized composite allotransplantation meeting was held in 2007 to standardize criteria for the characterization and reporting of severity and types of rejection. As a result, the 2007 Banff VCA working classification for skin allograft pathology was formalized and now serves as the standard for diagnosis of VCA rejection. Similar to other working classification systems, strengths and limitations have been identified including the adequacy of the specimen, the definition of severity between grades, the reproducibility, the adequacy of the specimens, the types of rejection, and the integration of newer technologies such as molecular and genomic approaches. Although a relatively few number of cases have been performed and followed up to date, additional phenotypes such as antibody‐mediated rejection, fibrosis, atrophy, and vascular changes are being reported and characterized based on accumulated experience in the field of VCA and parallels with other solid organs. This study aims to consider strengths and limitations of the Banff VCA working system and highlights ongoing challenges and opportunities available related to histopathology in this emerging field of transplantation.

Pathophysiology of dermatitis herpetiformis: a model for cutaneous manifestations of gastrointestinal inflammation.

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease in which antigen presentation in the gastrointestinal mucosa results in cutaneous IgA deposition and distinct, neutrophil-driven cutaneous lesions. Our findings suggest that the qualitatively different immune response to gluten in the intestinal mucosa of patients with DH results in minimal clinical symptoms, allowing the continued ingestion of gluten and the eventual development of DH. Our model may provide a new way to understand the pathogenesis of other skin diseases associated with gastrointestinal inflammation such as pyoderma gangrenosum or erythema nodosum, or explain association of seronegative inflammatory arthritis with inflammatory bowel disease.